"One-Pot" multicomponent approach to indolizines and pyrido[1,2-a ]indoles

Article abstract of DOI:10.1021/ol200883w

A new synthetic protocol for efficient and regiospecifc assembly of indolizines and pyrido[1,2-a]indoles by coupling of substituted methyl bromides and alkynes with corresponding pyrrole-2-carboxaldehyde and 1H-indole-2- carboxaldehyde has been developed.

Full text of DOI:10.1021/ol200883w

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2792–2794
“One-Pot” Multicomponent Approach to
Indolizines and Pyrido[1,2-a]indoles
€
Huajian Zhu, Joachim Stockigt, Yongping Yu, and Hongbin Zou*
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, P. R. China
zouhb@zju.edu.cn
Received April 5, 2011
ABSTRACT
A new synthetic protocol for efficient and regiospecifc assembly of indolizines and pyrido[1,2-a]indoles by coupling of substituted methyl
bromides and alkynes with corresponding pyrrole-2-carboxaldehyde and 1H-indole-2-carboxaldehyde has been developed. Additionally, a
possible mechanism for the reaction is proposed.
During the past decade, the pharmacological potential
of indolizines has been well recognized. Many indolizines
have shown important biological activities, including anti-
HIV,1 anti-inflammatory,2 5-HT3 receptor antagonist,3
H3 receptor antagonist,4 as well as usage as molecular
probes.5 As a result, a variety of methods for their synthesis
have emerged6 and most synthetic strategies require start-
ing from pyridinium N-methylides6aÀd or pyridines with
specific C2 functionalization.6eÀn In recent published re-
ports, the transition-metal-catalyzed intramolecular reac-
tion of alkynylpyridines is the primary method of choice,
but often, this approach suffers from limitations such as
expensive metal catalyst or substrate complexity.6eÀk,7
Herein, we report a facile, efficient, and regiospecific
approach to provide indolizines with additional functional
diversity using commercially available starting material.
This “one-pot” three-component coupling reaction was
also found to be suitable for the synthesis of pyrido[1,2-
a]indoles which possess a wide array of important biolo-
gical properties.8 We also present two interesting examples
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r
10.1021/ol200883w
Published on Web 04/21/2011
2011 American Chemical Society

of tricyclic heterocycles synthesized using pyrrole-2-car-
boxaldehyde and special substrates.
Table 2. Scope of Coupling Reactiona
Initially, the pyrrole-2-carboxaldehyde a, alkyne b01,
and 2-bromo-1-phenylethanone c01 were selected as a
model system to optimize the reaction conditions. Differ-
ent solvents were examined first, and the results indicated
that solvent plays a major role in the cycloisomerization
transformation (Table 1, entries 1À5).
no.
R1
R2
R3
product d yieldb (%)
1
2
3
4
COOMe MeO C6H5CO
d01
d02
d03
d04
d05
d06
d07
d08
d09
d10
d11
d12
d13
d14
d15
d16
d17
d18
d19
d20
d21
d22
d23
d24
d25
d26
d27
d28
d29
d30
d31
72
85
63
65
61
59
53
78
89
62
88
80
86
78
60
64
97
87
98
82
63
68
85
76
82
75
51
66
52
42
53
Table 1. Optimization of Reaction Conditionsa
COOEt
EtO
C6H5CO
H
H
MeO C6H5CO
C6H5 C6H5CO
MeO C6H5CO
MeO 4-Br-C6H5CO
5c Me
6c Me
7c C6H5
EtO
4-Br-C6H4CO
8
9
COOMe MeO 4-Br-C6H4CO
COOEt
H
EtO
4-Br-C6H4CO
no.
base
solvent
temp (°C)
yieldb (%)
10
MeO 4-Br-C6H4CO
11 COOMe MeO 4-Me-C6H4CO
12 COOMe MeO 4-Cl-C6H4CO
13 COOMe MeO 4-MeO-C6H4CO
14 COOMe MeO C3H5CO
15 COOMe MeO COOEt
16c COOMe MeO CN
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Et3N
MeCN
C2H5OH
DCM
touene
DMF
25
25
25
25
25
25
25
25
40
50
65
38
trace
0
3
4
0
5
75
6
DMF
15
17 COOEt
18 COOEt
19 COOEt
20 COOEt
21 COOEt
22c COOEt
EtO
EtO
EtO
EtO
EtO
EtO
4-Me-C6H4CO
4-Cl-C6H4CO
4-MeO-C6H4CO
C3H5CO
7
DMF
30
8
NaH
DMF
trace
91
9
K2CO3
K2CO3
K2CO3
DMF
10
11
DMF
DMF
98
89
COOEt
CN
a Reaction conditions: pyrrole-2-carboxaldehyde (0.2 mmol, 1.0
23
24
25
26
27
H
H
H
H
H
MeO 4-Me-C6H4CO
MeO 4-Cl-C6H4CO
MeO 4-MeO-C6H4CO
MeO C3H5CO
equiv), 2-bromo-1-phenylethanone (0.2 mmol, 1.0 equiv), alkyne (0.24
mmol, 1.2 equiv), base (0.4 mmol, 2.0 equiv), 1.5 mL of solvent, 12 h.
b Determined by high-performance liquid chromatography based on the
disappearance of the starting pyrrole-2-carboxaldehyde. The most
successful entry is highlighted in bold.
MeO C3H7CO
28c Me
29c Me
30c Me
31c C6H5
MeO 4-MeO-C6H4CO
MeO C3H5CO
Next, we tested the three-component coupling reaction
in the presence of various bases. The base also plays a
crucial role in the success of indolizine derivative d01
synthesis (Table 1, entries 5À8), and K2CO3 was found
to be the most favorable base for this transformation
(entry 5, 75%). The reaction efficiency was also assessed
with varying reaction temperatures. Significant improve-
ment in the reaction yield was observed when the tempera-
ture was increased from 25 to 50 °C (75% to 95%, Table 1,
entries 5 and 10). However, further increase of temperature
resulted in a slight decrease in the yield (Table 1, entry 11).
With the optimized conditions in hand, the scope and
limitations of the coupling reaction were next examined by
employing various substituted methyl bromides and al-
kynes (Table 2). The alkynes presented in Table 2 all have
at least one electron-withdrawing group. We also exa-
minded alkynes such as allylene, cyclopropylacetylene,
phenylacetylene, and ethynyltrimethylsilane, and no reac-
tion was observed. This demonstrates the importance of an
electron-withdrawing group on the alkyne for the reaction.
Notably, the alkynes bearing two electron-withdrawing
groups gave the desired products with better isolated yields
than those with only one electron-withdrawing group
(Table 2, entries 1À4, 8À27). An additional observation
MeO CN
EtO
C3H5CO
a Reaction were performed in anhydrous DMF at 50 °C in the
presence of base. b Isolated yield. c The reaction was performed at 90 °C.
was that no reaction took place under the studied reaction
conditions if one terminal of alkyne contained a methyl or
phenyl group (Table 2, entries 5À7 and 28À31). In these
cases, the desired products d05À07 and d28À31 were
obtained in moderate yields when we raise the reaction
temperature to 90 °C. Unexpectedly, only one single
regioisomer with the R1 group adjacent to the R3 group
was observed (entries 3À7, 10, and 23À31) when asym-
metric alkynes were utilized for the synthesis of corre-
sponding indolizines. The structures were confirmed by
HRMS and NMR spectra data.
As presented in Table 2, the generality of this process
was expanded by the utilization of a variety of substituted
methyl bromides. The methyl bromides with a substituted
phenyl acyl group produced better reaction efficiencies
than those with substituents of ester, alkyl acyl, and
cycloalkyl acyl (Table 2, entries 11À27), while the sub-
stituent of the poor electron-withdrawing cyano group
Org. Lett., Vol. 13, No. 10, 2011
2793

required a higher reaction temperature (Table 2, entries 16,
22, and 30). Additionally, the electronic property of the
substituent on the aryl ring also has some influence on the
efficiency of cycloisomerization (entries 11À13, 17À19).
For instance, in entries 17À22, the isolated yields vary
from 63% to 98% in which c19 with a electron-rich aryl
ring quantitively transformed to d19 (98%, entry 19) while
c21 with an ester substituent cyclized to d21 in a moderate
yield (63%, entry 21).
afford the corresponding pyrido[1,2-a]indoles (Table 3).
This might be ascribed tothe decrease inelectrondensity of
nitrogen in the indole ring as compared to pyrrole-2-
carboxaldehyde.
On the basis of the results presented above, we pro-
posed the following possible mechanism for this reaction,
as shown in Scheme 1. In the presence of base, nucleo-
philic attack of the nitrogen in pyrrole-2- carboxaldehyde
to the substituted methyl bromide lead to N-substituted
pyrrole-2-carboxaldehyde a-b, followed by a further nu-
cleophilic attack of a-b, to the alkyne c. Subsequently, the
newly formed active intermediate d-1 undergoes an in-
tramolecular cycloisomerization to afford the desired
product d.
Table 3. Synthesis of Pyrido[1,2-a]indolesa
Interestingly, when 1-bromo-3-methylbutan-2-one and
alkynes with two ester groups were chosen as substrates,
new tricyclic heterocycles (g) were formed in moderate
yields (Scheme 2). The possible mechanism is shown in
Scheme 2 which proceeds through a spontaneous intra-
molecular cyclization similar to the one proposed in
Scheme 1.
no.
R1
R2
R3
product f yieldb (%)
1
2
3
4
5
6
COOMe OMe C6H5CO
f01
f02
f03
f04
f05
f06
46
41
58
40
49
45
COOMe OMe 4-Br-C6H4CO
COOMe OMe 4-MeO-C6H4CO
COOMe OMe C3H5CO
COOEt
H
OEt
C6H5CO
Scheme 2. Synthesis of Tricyclic Heterocycles from Pyrrole-2-
carboxaldehyde
OMe C6H5CO
a Reactions were performed in anhydrous DMF at 110 °C in the
presence of base. b Isolated yield.
In order to gain further insight about this process, 1H-
indole-2-carboxyaldehyde e was also utilized in this trans-
formation providing access to the pyrido[1,2-a]indole scaf-
fold (f, Table 3). Initial attempts with the same conditions
as indolizines syntheses resulted in no observation of
pyrido[1,2-a]indoles being formed. Consistent with our
initial observations for the synthesis of the indolizines
(Table 2, entry 5À7 and 28À31), the cycloisomerization
transformations were achieved at a higher temperature to
In summary, we have developed a new synthetic proto-
col for efficient and regiospecific assembly of indolizines
and pyrido[1,2-a]indoles from commercially available
starting materials. We also demonstrated two interesting
and special cases for tricyclic heterocycle synthesis from
pyrrole-2-carboxaldehyde.
Scheme 1. Possible Mechanism for the Synthesis of Indolizines
Acknowledgment. We thank the National Natural
Science Foundation of China (20802066) and National
Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” of China
(2009ZX09501-010) forthefinancialsupport. Weacknowl-
edge Dr. M. Giulianotti for proofreading the manuscript.
Supporting Information Available.
Experimental
procedures and compound characterization data of all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
2794
Org. Lett., Vol. 13, No. 10, 2011